Carvedilol-galenics

ABSTRACT

The invention relates to a process for the preparation of fast-dissolving pharmaceutical preparations from difficultly soluble active substances, wherein an aqueous suspension is made from active substance and one or more water-soluble adjuvants and then the resulting aqueous suspension is processed, with removal of the water, by methods conventional per se, to form solid pharmaceutical preparations. The invention also relates to fast-dissolving pharmaceutical preparations of active substances having a dissolution rate of at least 70% after 30 minutes, prepared in accordance with the process of the invention.

[0001] The invention relates to a process for the preparation offast-dissolving pharmaceutical preparations from difficultly solubleactive substances which tend to agglomerate, with a dissolution rate ofat least 70% after 30 minutes, and pharmaceutical preparations made bythis process.

[0002] In the case of drugs which cannot develop their action in thegastrointestinal zone itself, release from the drug form in thegastrointestinal tract and the subsequent resorption are the necessarycondition for a therapeutic effect. Problems arise in this connectionwith those active substances which, because of their poor solubility ortheir low dissolution speed, attain so low a concentration in thegastrointestinal tract in the aqueous medium or because of obstructedrelease from the system of the other adjuvants, that the dissolution ofthe active substance is the step which determines the rate in connectionwith the resorption. Because of the low resorption speed as a result,such active substances do not then achieve adequate bioavailability.Problematic drugs of this kind are normally said to be active substanceswhich have a solubility of less than 5 g/l water or the dissolution rateof which from a solid drug form is less than 50% after 30 minutes. Thesolubility and release rate are determined by standard methods, e.g. inaccordance with the paddle method of USP XXII.

[0003] Since there are relatively narrow limits to increasing thesolubility due to the nature of the active substances (examples are saltformation, derivatisation with solubility-improving groups which do notinfluence the action or which are split off again in the blood, theproduction of soluble solvates or other complexes or conversion tohigh-energy and hence better-soluble crystal forms), the main attentionin the past has been devoted to increasing the dissolution speed. Since,according to the known Fick's laws, the speed of dissolution isproportional to the area of the active substance, the concentrationgradient of the active substance between the surface of the particlesand the solution, and the thickness of the diffusion film adhering tothe particles, there are three options for increasing the dissolutionspeed in the case of diffusion coefficients determined by the activesubstance and solution medium.

[0004] The thickness of the diffusion layer is practically dependent onthe movement of the active substance particles in the gastrointestinaltract and hence capable of relatively little influencing. There arerelatively narrow limits to increasing the concentration gradients,since the most rapid possible distribution of the active substanceparticles over the gastrointestinal area available can be obtained onlyby the addition of disintegrating agents and surfactants. For thisreason, the largest possible active substance area is produced. Forexample, active substances are converted by fine comminuting or rapidprecipitation into a microcrystalline or amorphous state, or else amolecular-dispersed, amorphous or microcrystalline distribution of theactive substance in the adjuvant is obtained by dissolving in the meltor dissolving a readily soluble adjuvant followed by solidification orevaporation of the solvent.

[0005] However, it has been found that the microcrystalline or amorphousactive substance particles obtained by comminuting or precipitation tendto recrystallise due to their very high surface energy duringprocessing, particularly under pressure or the addition of solvents andin the case of fairly long storage, so that the surface area and hencethe dissolution speed falls off uncontrollably. It has also been foundthat fine particles tend to combine to form relatively solidagglomerates which even when introduced into a solvent can be separatedonly with difficulty and therefore behave like a correspondingly largerparticle of lower specific surface area. Consequently, such activesubstances are comminuted together with the soluble adjuvants in excessin order thus to achieve physical separation of the active substanceparticles by excipient particles. However, even with a considerableexcess of adjuvants, recrystallisation or agglomeration of the activesubstance particles cannot be completely prevented by these steps, sothat the dissolution speed of such preparations is not optimal, andparticularly not time-independent.

[0006] The second possibility of obtaining finely divided activesubstances is to divide the active substance in a matrix of ahydrophilic readily soluble adjuvant. In this connection, water-solublepolymers have proved particularly suitable, such as polyvinylpyrrolidone, polyethylene glycol and others. Depending on the propertiesof the active substance, this can be achieved by dissolving the activesubstance in a melt of the adjuvant and dispersing this either by spraysolidification or by comminuting the solidified melt, whereupon theresultant particles are processed into granulates or tablets, ifrequired after mixing with other adjuvants. If the active substance isnot adequately soluble, or if it is damaged by the adjuvant substancemelt temperature, the two components can also be dissolved in a suitablesolvent from which they are recovered in the form of a substantiallyhomogeneous mixture after removal of the solvent. A disadvantage of thisprocess in particular is that the difficult solubility of the activesubstance in water means that practically only organic solvents can beused, the processing of which is accompanied by known problems ofworkplace safety and environmental pollution.

[0007] Moreover, because of the solubility conditions, not all activesubstances can be processed in this way, and the resulting amorphous ormolecular-dispersed distributions of the active substance in theadjuvant matrix tend to recrystallise and hence tend to change thedissolution speed of the active substances.

[0008] The object of the invention was to develop an efficient andenvironmentally friendly process for the preparation of fast-dissolvingpharmaceutical preparations from difficultly soluble active substanceswhich normally have a dissolution rate of less than 50% after 30 minutesand tend to agglomerate or recrystallise. Another object of theinvention was to prepare fast-dissolving pharmaceutical preparations ofdifficultly soluble active substances such as, for example, carvedilol.

[0009] The problem underlying the invention is surprisingly easilysolved by the preparation of an aqueous suspension from difficultlysoluble active substance and one or more water-soluble adjuvantsfollowed by processing of this aqueous suspension to form solidformulations with removal of the water.

[0010] More particularly, the invention relates to a process for thepreparation of fast-dissolving pharmaceutical preparations fromdifficultly soluble active substances having a dissolution rate of atleast 70% after 30 minutes, wherein an aqueous suspension is preparedfrom the active substance and one or more water-soluble adjuvants andthen the resulting aqueous suspension is processed, with removal of thewater, by conventional processes to form solid pharmaceuticalpreparations.

[0011] According to the invention, difficultly soluble activesubstances, such as, for example, carvedilol, are mixed with an aqueoussolution of one or more suitable adjuvants and then the water isstripped off. It has been found particularly advantageous to use theactive substance in a particle diameter of less than 500 μm, preferablya particle diameter of less than 250 μm, particularly preferably with aparticle diameter of less than 100 μm. The active substance ismechanically comminuted for the purpose by methods known per se.

[0012] In one preferred embodiment, carvedilol or4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole are used asactive substances.

[0013] The term “adjuvants” according to the invention means any readilywater-soluble pharmaceutically unobjectionable substances which do nothave a negative reaction with the active substance. Thus allconventional binders, fillers, disintegrating agents and/or surfactants(wetting agents, surface-active agents) are used. Mono anddisaccharides, for example saccharose, glucose and lactose; oligo andpolysaccharides, for example starch; sugar alcohols, for examplemannitol and sorbitol; readily water-soluble cellulose derivatives, suchas, for example, methylhydroxypropyl cellulose; polyvinylpyrrolidonesand polyethylene glycols are preferred. In addition, all other knownpharmaceutical adjuvants can be used.

[0014] Readily water-soluble adjuvants are preferred since, depending onthe solubility of the adjuvant, corresponding quantities of water haveto be removed again. To avoid high expenditure in removing the water,the quantity of adjuvant is therefore kept as low as possible.

[0015] Thus the active substance/adjuvant ratio in the dry substance inthe suspension is in the range from 1:0.01 to 1:500, preferably in therange 1:0.1 to 1:50, particularly preferably 1:0.1 to 1:10, depending onthe type and magnitude of the formulation and the quantity of necessarysubstances and excipients.

[0016] If required, surfactants are added to the aqueous suspension ofthe difficultly soluble active substance, the ratio of active substanceto surfactant being in the range of up to 1:1, preferably up to 1:0.3,and up to 1:0.05 in a particularly preferred embodiment.

[0017] The surfactants used may be both ionic and non-ionic, for examplebenzalkonium chloride, polyoxyethylene polyoxypropylene copolymers (e.g.Pluronic F68), alkylsulphates, preferably sodium dodecyl sulphate andstearates, such as polyethylene glycol-400-stearate (Myrj).

[0018] According to one embodiment of the invention, a surfactant isdissolved in water and the difficultly soluble active substance isadmixed in this solution together with one or more adjuvants.

[0019] In addition, a water-insoluble excipient can be additionallyadmixed in the aqueous suspension of active substance and adjuvants, orelse the aqueous suspension is applied to a water-insoluble excipient ofthis kind. The proportion of water-soluble excipient in relation to theactive substance can be up to 50:1. In a preferred variant thedifficultly soluble active substance is stirred into an aqueous adjuvantsolution together with the water-insoluble excipient and, if required,together with other water-soluble adjuvants.

[0020] The water-insoluble excipients are preferably highly dispersedsilicon dioxide or aluminium oxide. The proportion of highly dispersedsilicon dioxide or aluminium oxide used is up to 20%, based on the solidactive substance.

[0021] The conversion of the preferably aqueous suspension into solidpharmaceutical preparations following upon the preparation of thepreferably aqueous suspension is effected by methods known per se. Forexample, a preferred variant is spray drying, as a result of which,depending on the dryer size and the type of atomisation, powders orgranulates or obtained. These powders or granulates (powders after priorgranulation possibly) are processed further into solid drug forms suchas, for example, tablets, dragees, capsules, pellets or globules. Ifrequired, other conventional adjuvants, for example fillers such ashydrophilic carbohydrates, such as sugar for example, preferablyglucose, lactose and saccharose, e.g. sugar alcohols, such as mannitoland sorbitol; for example starch and starch derivatives; binders, suchas, for example, gelatin, microcrystalline cellulose, polyvinylpyrrolidone derivatives and L-HPC; disintegrating agents, for examplecarboxymethyl cellulose, starch 1500 and sodium carboxyrmethyl starch,ionic and non-ionic surfactants, lubricants, for example talcum orpolyethylene glycols; lubricating agents and mould release agents, forexample magnesium or calcium stearate, stearic acid, 1-hexadecanol; flowregulators, for example highly dispersed silicon dioxide, and talcum mayalso be admixed if required.

[0022] In other variant, the aqueous suspension is used directly for wetgranulation, e.g. in a fluidised bed or in a high speed mixer, possiblywith the said conventional adjuvants, and the resulting granulate isdried and further processed in manner known per se. By evaporation ofthe water the active substance particles are initially coated with alayer of the adjuvants dissolved in the suspension. In addition, thesecoated particles are combined with the original adjuvants to form largerunits. If the suspension volume is high in relation to the originaladjuvant volume, wet granulation is advantageously carried out in anumber of steps, i.e., intermediate drying steps are interposed duringgranulation.

[0023] In another variant of the invention, the suspension containingthe active substance is applied to pellets or globules or used for thepreparation of pellets.

[0024] In another variant of the process, a solid pharmaceuticalpreparation is made by spray drying from the active substance suspendedin meltable adjuvants, and this suspension can as a variant also containa highly dispersed excipient, e.g. silicon dioxide.

[0025] The process according to the invention has the advantage thatthere is no need to use organic solvents or high temperatures.

[0026] It has been found that the active substance in the aqueoussuspension prepared and used according to the invention is present in astable initial crystal form which does not change during processing sothat changes in the crystal modification in solid pharmaceuticalpreparations of the difficultly soluble active substances prepared bythe process according to the invention are substantially eliminated.This means that there are no significant conversion processes oruncontrolled recrystallisation to other crystal modifications duringstorage of the forms of administration. The adjuvants dissolved in thesuspension are obtained in a partially or fully amorphous substancemixture after drying. This structure of the substance mixture issubstantially maintained even in the case of storage for many years, andthis has been confirmed, for example, by X-ray diffraction tests.

[0027] The subject matter of the present invention is also afast-dissolving pharmaceutical preparation of a difficultly solubleactive substance, preferably carvedilol, with a dissolution rate of atleast 70% after 30 minutes, the active substance preferably beingembedded in a partially or fully amorphous substance mixture or beingenclosed in a partially or fully amorphous substance mixture.

[0028] The solid pharmaceutical preparations made according to theinvention have a surprisingly high dissolution rate of at least 70%,preferably at least 80% after 30 minutes. More particularly, with theprocess according to the invention it is possible to prepare solidpharmaceutical preparations of carvedilol or4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole, acetatewith this dissolution rate.

[0029] In comparison to this, the dissolution rates of the puresubstances or powders of these active substances with hydrophilicadjuvants are in some cases far below 50% after 30 minutes. Due to thehigh tendency of these active substances to agglomerate, increasing thesurface area by comminuting does not result in a significant improvementin the dissolution speed, even with the addition of hydrophilicadjuvants. Accordingly, the granulates, tablets and capsules preparedwith the conventional methods and with conventional pharmaceuticaladjuvants also have unsatisfactory active substance dissolution rates.Even if tablets are prepared with micronised active substance, thedissolution rate after 30 minutes is below 50% (cf. Examples 1 and 2).

[0030] The preparations made according to the invention can also be usedas a basis for modified release preparations. Whereas, for example, inthe case of conventional retard forms with difficultly soluble activesubstances the active substance release is determined not only by theretarding adjuvants but substantially also by the dissolution behaviourof the difficultly soluble active substances, when the preparationsaccording to the invention are used it is possible to achieve controlledrelease dependent solely on the retarding adjuvants.

[0031] The invention will be explained in detail hereinafter withreference to Examples.

EXAMPLE 1 (COMPARATIVE EXAMPLE)

[0032] In-vitro dissolution rates of the active substances4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole (acetateform) (A) and carvedilol (B), or the comminuted forms with hydrophilicadjuvants—in powder form. In-vitro dissolution rate after minutes in %Formulation mg Process 10 20 30 60 Active Pure substance 31 43 50 58substance A Active 80 Micronised 40 46 53 62 substance A Lactose D 80 60together Active Pure substance 36 46 49 56 substance B Active 30Micronised 20 26 27 29 substance B Saccharose 30 together Active 30Micronised 24 26 27 29 substance B Lactose D 80 30 together

EXAMPLE 2 (COMPARATIVE EXAMPLE)

[0033] Dissolution Rate of Tablets with Micronised Active Substance

[0034] Jet comminuted carvedilol/lactose was mixed with otherhydrophilic adjuvants and disintegrating agents such as lactose,poly(1-vinyl-2-pyrrolidone), cross-linked, andpoly-(1-vinyl-2-pyrrolidone), granulated with a polyethylene stearatesolution (Myrj 52), dried and screened. The granulate was mixed withconventional pharmaceutical adjuvants, such aspoly(1-vinyl-2-pyrrolidone), cross-linked, highly dispersed silicondioxide and magnesium stearate and pressed into tablets.

[0035] In-vitro dissolution rate of carvedilol after minutes in %: 10 2030 60 min 22 36 42 50 %

[0036] The in-vitro dissolution rates in this and the following exampleswere determined in accordance with USP XXII, paddle method in an aqueousbuffer pH 4.5

EXAMPLE 3

[0037] Carvedilol Suspension for Spray Drying.

[0038] 75 mg Myrj 52 were dissolved in 700 g of water purified, and then300 g carvedilol, 300 g saccharose and hydroxypropyl methyl cellulosewas mixed into the solution with a high-speed stirrer. The aqueoussuspension was spray dried.

[0039] In-vitro dissolution rate: 10 20 30 60 min 73 81 83 86 %

EXAMPLE 4

[0040] Carvedilol Tablets

[0041] 69 g of the product spray-dried in accordance with Example 3 weremixed with hydrophilic adjuvants (e.g. lactose, saccharose, mannitoletc.), disintegrating agents (e.g. sodium carboxymethyl starch,poly(1-vinyl-2-pyrrolidone), cross-linked, corn starch), highlydispersed excipient (silicon dioxide, highly dispersed, aluminium oxide,etc.) and binder poly(1-vinyl-2-pyrrolidone) and granulated with water.The wet granulate was dried, screened and then pressed with a mouldrelease agent (if required addition of a flow agent and/ordisintegrating agent), to form tablets having an active substancecontent of 30 mg and a final weight of 180 mg.

[0042] In-vitro dissolution rate from the tablets: 10 20 30 60 min 81 8896 98 %

EXAMPLE 5

[0043] Carvedilol Capsules

[0044] The product spray-dried in accordance with Example 3 was mixedwith hydrophilic adjuvants, if required flow agents, disintegratingagents and mould release agents, and packed in capsules on conventionalcapsule filling machines.

[0045] In-vitro dissolution rate from the capsule filler: 10 20 min 95100 %

EXAMPLE 6

[0046] Carvedilol Granulation Suspension

[0047] 75 mg Myrj 52 were dissolved in 700 g water purified, and then300 g carvedilol and 300 g saccharose were mixed into the solution witha high-speed stirrer.

EXAMPLE 7

[0048] Carvedilol Tablets

[0049] The aqueous granulation suspension according to Example 6 wasabsorbed on a mixture of hydrophilic adjuvants, disintegrating agent,highly dispersed excipient and binder, dried and screened.

[0050] Using a mould release agent, if required also a flow agent anddisintegrating agent, tablets were made in an end weight of 180 mg witha content of 30 mg carvedilol.

[0051] In-vitro dissolution rate: 10 20 30 60 min 78 90 93 97 %

[0052] The active substance suspension according to the invention, orthe spray products or granulates made therefrom, may contain asurfactant (e.g. polyoxyethylene stearate) in the form of Myrj 52 orMyrj 53. In the suspension, the ratio of active substance to surfactantcan be in the range of up to 1:1, preferably up to 1:0.3.

[0053] If required, the adjuvant hydroxypropyl methyl cellulose(Pharmacaot 603) may be added in the spray drying suspension to improvethe spraying and product properties.

EXAMPLE 8 4-[2-Hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indoleacetate

[0054] Suspension for Spray Drying

[0055] The active substance4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole acetate wasstirred into an aqueous poly(1-vinyl-2-pyrrolidone) solution togetherwith a highly dispersed excipient (e.g. highly dispersed silicon oxide)and a disintegrating agent (e.g. poly(1-vinyl-2-pyrrolidone),cross-linked, Primojel) and homogenised.

[0056] The aqueous suspension was spray dried.

[0057] In-vitro dissolution rate: 10 20 30 60 min 93 97 99 100 %

EXAMPLE 9 4-[2-Hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indoleacetate

[0058] Granulation Suspension

[0059] The aqueous substance was stirred into an aqueouspoly(1-vinyl-2-pyrrolidone) solution together with a highly dispersedexcipient (e.g. highly dispersed silicon dioxide) and a disintegratingagent (e.g. poly(1-vinyl-2-pyrrolidone), cross-linked, Primojel) andhomogenised.

[0060] The aqueous granulation suspension was absorbed on a mixture ofhydrophilic adjuvants, disintegrating agents and highly dispersedexcipient, dried and screened.

[0061] The application of the granulation suspension to the adjuvantmixture was carried out in a conventional mill, granulator or byspraying in a fluidised bed.

[0062] In-vitro dissolution rate of4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole acetatefrom granulate: 10 20 30 60 min 71 88 94 97 %

EXAMPLE 10 4-[2-Hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indoleacetate

[0063] Tablets and Capsules

[0064] Both the spray-dried suspension according to Example 8 and thegranulate according to Example 9, obtained by absorbing the aqueousgranulation suspension on special adjuvants, can be processed by methodsknown per se to form tablets, film tablets, dragees, pellets, hardgelatin capsules or soft gelatin capsules.

[0065] In-vitro dissolution rate of4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole acetatefrom tablets: 10 20 30 60 min 84 92 94 96 %

1. A process for the preparation of fast-dissolving pharmaceuticalpreparations from difficultly soluble active substances with adissolution rate of at least 70% after 30 minutes, wherein an aqueoussuspension is made from the active substance and one or morewater-soluble adjuvants, and then the resulting aqueous suspension isprocessed, with removal of the water, by methods know per se, to formsolid pharmaceutical preparations.
 2. A process according to claim 1,wherein the active substance used is carvedilol or 4-[2-hydroxy-3-[4-(phenoxymethyl)piperidino]-propoxy]-indole.
 3. A process according toclaim 1 or 2, wherein the active substance has a particle diameter ofless than 500 μm, preferably less than 250, more particularly less than100 μm.
 4. A process according to any one of claims 1 to 8, wherein thewater-soluble adjuvants used are binders, fillers, disintegrating agentsand/or surfactants which are conventional per se.
 5. A process accordingto any one of claims 1 to 4, wherein the ratio of active substance toadjuvant in the dry substance in the suspension is 1:0.01 to 1:500,preferably 1:0.1 to 1:50.
 6. A process according to any one of claims 1to 5, wherein a surfactant is added to the aqueous suspension, the ratioof active substance to surfactant being in the range of up to 1:1,preferably up to 1:0.3.
 7. A process according to any one of claims 1 to6, wherein the surfactant is dissolved in water and then the activesubstance is admixed together with one or more adjuvants.
 8. A processaccording to any one of claims 1 to 7, wherein a water-insolubleexcipient is admixed in the aqueous suspension or the suspension isapplied to the excipient.
 9. A process according to any one of claims 1to 6, wherein the active substance is stirred together with thewater-insoluble excipient into an aqueous adjuvant solution, if requiredtogether with other water-soluble adjuvants.
 10. A process according toclaim 8 or 9, wherein the water-insoluble excipient is highly dispersedsilicon dioxide or aluminium oxide.
 11. A process according to any oneof claims 1 to 10 wherein solid pharmaceutical preparations are madefrom the aqueous suspension by spray-drying.
 12. A process according toany one of claims 1 to 10, wherein solid pharmaceutical preparations aremade from the aqueous suspension by wet granulation, preferably in afluidised bed or a high speed mixer.
 13. A process according to any oneof claims 1 to 10; wherein solid pharmaceutical preparations are made byspray solidification from the active substance suspended in meltableadjuvants.
 14. Fast-dissolving pharmaceutical preparation of adifficultly soluble active substance having a dissolution rate of atleast 70% after 30 minutes, prepared by any one of claims 1 to
 13. 15.Fast-dissolving pharmaceutical preparation of a difficultly solubleactive substance having a dissolution rate of at least 70% after 30minutes, made by any one of claims 1 to 13, wherein the active substanceis embedded in a partially or fully amorphous substance mixture or isenclosed in a partially or fully amorphous substance mixture.
 16. Apharmaceutical preparation according to claim 14 or 15, containingcarvedilol as active substance.
 17. Use of the process according to anyone of claims 1 to 13 for the preparation of fast-dissolvingpharmaceutical preparations of a difficultly soluble active substancehaving a dissolution rate of at least 70% after 30 minutes.
 18. Theinvention as described above.